A variety of studies have shown that different levels of breast cancer risk can be reliably distinguished on the basis of histologic criteria in women with benign breast disease. See, for example, London et al. JAMA 1992, 267:941-4; Palli et al. Int J Cancer 1991, 47:703-6; Dupont et al. N Engl J Med 1985, 312:146-51; Dupont et al. Cancer 1993, 71:1258-65; Hartmann et al. N Engl J Med 2005, 353:229-37. Although the conclusions of these studies vary in some respects, results from the two most recent of these references are reviewed herein. The Hartmann et al. (N Engl J Med 2005, 353:229-37) study followed 9087 women for a median of 15 years. The histologic findings were as follows: nonproliferative lesions were noted in 67 percent of women, proliferative lesions without atypia were noted in 30 percent, and atypical hyperplasia was noted in 4 percent. At the closure of the study, 707 study participants had developed breast cancer. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), an increased risk that persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for non-proliferative lesions. A family history of breast cancer was identified as a risk factor that was independent of histologic findings. These results indicate that non-proliferative lesions are linked to a slightly increased chance of developing breast cancer. The results of Dupont et al. (Cancer 1993, 71:1258-65) suggest that the presence of cysts (a type of non-proliferative disorder) significantly increases breast cancer risk, although this increase is largely restricted to patients with proliferative disease without atypia (PDWA). The Dupont et al. study further indicates that there is no evidence that the presence of cysts affects breast cancer risk in women without proliferative breast disease (PD) or in those with atypical hyperplasia (AH). A fourfold increase in breast cancer risk is, however, observed in women with both cysts and familial history (FH).
Breast cancer is the most common cancer in women and the second leading cause of cancer-related mortality in women. About 10% of breast cancer cases cluster in families. Mutations in the breast cancer susceptibility (BRCA) genes are correlated with a high percentage of these familial cases. Indeed, BRCA1 mutations account for the most common form of genetically inherited breast cancer. Germline mutations of BRCA1 have been detected in approximately 90% of familial breast and ovarian cancers and approximately 50% of familial breast cancer alone (Hill et al. 1997 Br. J. Surg. 84, 1334-1339; Casey. 1997. Curr. Opin. Oncol. 9, 88-93. Women that inherit germ cell mutations of BRCA1 are at up to 80% risk of developing breast cancer and 50% risk of developing ovarian cancer. BRCA mutation carriers are also typically diagnosed with invasive breast cancer about ten years earlier than patients presenting with sporadic breast cancer. BRCA1 associated cancers, moreover, exhibit distinct histopathology, immunohistochemistry, cytogenetics, and gene expression profiles that differ from those of either non-familial breast cancer cases or BRCA2-related breast cancer.
Even though most BRCA1 mutations lead to estrogen receptor negative breast cancer, treatment with estrogen increases cancer risk in Brca1 disease. Also there is a high degree of hyperplastic lesions in women with mutations in the BRCA1 gene when their breast tissue is examined following prophylactic mastectomies performed to avoid development of breast cancer (Hoogerbrugge N J Clin Oncology 2003, 41-45).
Women with certain hyperplastic lesions of the breast are at high risk for breast cancer. There is clinical evidence that treatment with tamoxifen can prevent the development of cancer by about 50%. Tamoxifen treatment is problematic in that it has many side effects and makes women almost completely estrogen deficient as if they were menopausal. Serious side effects include uterine cancer, pulmonary embolism, strokes. Although well tolerated by some patients, many patients experience one or more unpleasant side effects and some experience life threatening complications as a result of tamoxifen treatment. Indeed, some patients consider the side effects of tamoxifen treatment to be unacceptable.
With respect to BRCA1 mutation carriers, however, even tamoxifen, which is effective in preventing most sporadic breast cancers, is not known to be an effective preventive measure (King M C et al, JAMA 2001 2251-2256). Due to their high risk for developing breast cancer and limited preventive options, many BRCA1 mutation carriers feel compelled to turn to prophylactic bilateral mastectomy as the only proven method for preventing development of breast cancer (Meijers-Heijboer, H N Eng J Med 2001 159-164). Bilateral oophorectomy is also an available option, but is known to be less protective (Rebbeck, T R et al J Natl Cancer Inst 1999, 1475-1479).
Antiestrogens or aromatase inhibitors have also been employed as a means of preventing breast cancer in women with preneoplastic breast lesions such as atypical hyperplasia or ductal carcinoma in situ (DCIS). While effective in women with atypical hyperplasia, these approaches may cause serious side effects and symptoms of menopause which can be intolerable, and also a high incidence of osteoporosis. Ruan et al. have proposed that inhibition of insulin-like growth factor 1 (IGF-I or IGF-1) activity might be able to substitute for estrogen inhibitors because IGF-I is essential for estrogen and progesterone action in the mammary gland (Ruan W et al (2005) Endocrinology 146(3):1170-1178).
Somatostatin and somatostatin-related peptides are a family of peptides that have broad spectrum biological actions and exert suppressive effects on a large variety of cells, usually functioning as inhibitors of hormone secretion. Naturally-occurring peptides have a short half life because they are rapidly inactivated by endogenous peptidases and therefore efforts have been made to develop more stable peptides. The three more extensively tested analogs are SMS 201-995 (octreotide), BIM 23014 (lanreotide) and RC-160 (vapreotide) (Lamberts S W J et al (1991) Endocrin Rev 12:450-482). Somatostatins bind somatostatin receptor(s), with subtypes SSTR-1 to SSTR-5 identified, cloned, and functionally characterized (Patel Y C et al (1995) Life Sci 57:1249-1265; Patel Y C et al (1996) Metabolism 45 (suppl 1):31-38; Reisine T and Bell G I (1995) Endocrin Rev 16:427-442; Buscail L et al (1995) PNAS USA 92:1580-1584; Bell G I and Reisine T (1993) Trends Neurosci 16:34-38). Octreotide (SandostatinR) and vapreotide have a low affinity for SSTR-1, a high affinity for SSTR-2, and relatively low affinity for SSTR-3 and SSTR-5.
Somatostatin analogs have an established role in the management of patients with pituitary and neuroendocrine tumors but only a potential role in the treatment of solid tumors, including breast cancer. In this tumor type in particular, somatostatin analogs showed limited activity either when used alone or when given in combination with tamoxifen or bromocriptine. Moreover, none of the randomized trials that compared the therapeutic value of the combination of octreotide and tamoxifen versus tamoxifen alone showed any advantage in favor of combined treatment (Pritchard K I et al (2011) Journal of Clinical Oncology, 29:3869-3876). Therefore, although the great majority of trials failed to show major side effects attributable to somatostatin analogs, the use of these compounds was limited to controlled trials (Boccardo, F. and Amoroso D. (2001) Chemotherapy 47:62-77).
The new somatostatin analog called SOM230 prevents mammary development in rats via two mechanisms gland (Ruan, W et al (2006) Mol Endocrinology 20(2):426-436). One of them is an inhibitory effect on growth hormone secretion from the pituitary which can cause reduction of serum IGF-I. The other is a direct inhibition of IGF-I action in the mammary gland as demonstrated by a reduction in IRS-1 phosphorylation in the mammary gland. It has been postulated that this effect of SOM230 is mediated by either somatostatin receptor subtype (SSTR) 3 or 5 and that this causes an increase in IGF binding protein 5 (IGFBP5) which in turn blocks the local action of IGF-I in the mammary gland (Ruan, W et al (2006) Mol Endocrinology 20(2):426-436).
There is clearly a need for improved modalities and compounds for prevention of progression to breast cancer in at-risk individuals. The compound tamoxifen, which is in use for breast cancer prevention, has significant side effects due to its blocking effect of circulating estrogen. While tamoxifen is administered to antagonize estrogen action at the estrogen receptor (ER) in the breast, its systemic effects trigger signs and symptoms consistent with menopause. An alternative treatment that would provide targeted preventive therapy, without causing symptoms or signs of estrogen deficiency.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.